Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene-specific
Cedrik Tekendo-Ngongang1, Babajide Owosela1, Maximilian Muenke1
1Medical Genetics Branch, National Human Genome Research Institutes, National Institutes of Health, Bethesda, Maryland.
Insights
Congenital heart disease (CHD) frequently co-occurs with holoprosencephaly (HPE), suggesting a shared genetic basis. However, specific HPE genes like ZIC2 showed no associated CHD in this study, indicating gene-specific relationships.
Area of Science:
- Developmental Biology
- Genetics
- Cardiology
Background:
- Holoprosencephaly (HPE) and congenital heart disease (CHD) often occur together in patients with genetic variants.
- Shared biological pathways, such as Hedgehog and Nodal signaling, regulate both brain and heart development.
- Understanding the genetic underpinnings of this comorbidity is crucial for patient care.
Purpose of the Study:
- To investigate the clinical and genetic basis of CHD comorbidity in individuals with HPE.
- To assess the frequency of CHD in a cohort of HPE patients undergoing targeted sequencing.
- To explore potential gene-specific relationships between HPE and CHD.
Main Methods:
- Clinical evaluation of individuals with various types of HPE.
- Targeted genomic sequencing to identify genetic variants.
- Cardiac phenotype assessment in 434 HPE patients.
Main Results:
- CHD was identified in 8% (33/434) of individuals with HPE, with 30% (10/33) having complex heart disease.
- Only four individuals had damaging variants in known HPE genes (STAG2, SIX3, SHH).
- No CHD cases were found in 37 individuals with pathogenic ZIC2 variants.
Conclusions:
- CHD is a frequent comorbidity in HPE, irrespective of identifiable genetic variants.
- The co-occurrence of HPE and CHD may be genetically driven and gene-specific.
- Further research is needed to elucidate the precise genetic mechanisms linking HPE and CHD.
Abstract:
Comorbidity of holoprosencephaly (HPE) and congenital heart disease (CHD) in individuals with genetic variants in known HPE-related genes has been recurrently observed. Morphogenesis of the brain and heart from very early stages are regulated by several biological pathways, some of them involved in both heart and brain development as evidenced by genetic studies on model organisms. For instance, downregulation of Hedgehog or Nodal signaling pathways, both known as major triggers of HPE, has been shown to play a role in the pathogenesis of CHD, including structural defects and left-right asymmetry defects. In this study, individuals with various types of HPE were investigated clinically and by genomic sequencing. Cardiac phenotypes were assessed in 434 individuals with HPE who underwent targeted sequencing. CHDs were identified in 8% (n = 33) of individuals, including 10 (30%) cases of complex heart disease. Only four individuals (4/33) had damaging variants in the known HPE genes STAG2, SIX3, and SHH. Interestingly, no CHD was identified in the 37 individuals of our cohort with pathogenic variants in ZIC2. These findings suggest that CHD occurs more frequently in HPE-affected individuals with or without identifiable genetic variants, and this co-occurrence may be genetically driven and gene-specific.
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